1. Field of the Invention
The present invention provides a method for preparation polymeric micelles and use thereof in pharmaceutical applications. The micelle, which is used as a carrier for hydrophobic drugs, is prepared via phase separation of a biodegradable polymeric composition containing a block copolymer having a hydrophilic poly(alkylene glycol) component and a hydrophobic biodegradable polymer component suspended in a poly(ethylene glycol) medium.
2. Related Art
Many important drugs are hydrophobic and have limited solubility in water. In order to attain the expected therapeutic effect from such drugs, it is usually required that a solubilized form of the drug be administered to a patient. Therefore, solubilization of a poorly water soluble drug is key technology in the preparation of a formulation for oral or parenteral, especially intravenous, administration of the drug. Common methods used for solubilization of poorly water soluble drugs are: i) dissolving the drug in a co-solvent of a water-miscible organic solvent and water; ii) modifying the drug to its salt form which is soluble in water; iii) forming a soluble drug-complex using a complexing agent; and iv) micellizing the drug in an aqueous medium with a surfactant. Leon Lachman, “The Theory and Practice of Industrial Pharmacy”, Lea & Febiger, Philadelphia, 1986.
Solubilization methods using surfactants, not requiring any changes in the chemical structure of a drug, have been widely used to solubilize various drugs. Non-ionic surfactants, e.g. polyoxyethylene sorbitan fatty acid esters(Tween®) and polyoxyethylene alkyl ethers(Brij™ or Myrj™), are commonly used as the surface active agents. European Patent EP 0645145 discloses a method of solubilizing a typical poorly water soluble drug, paclitaxel, by use of Cremophor EL™, a polyoxyethylene castor oil derivative. However, the use of these surfactants, is restricted due to toxic side effects such as hypersensitivity. They have limitations in that their poor ability to stabilize micelles can cause precipitation of the drug when the micellar solution is either stored or is to remain in place for an extended period of time.
Polymeric micelles have been recently investigated as potential carriers for hydrophobic drugs. Eur. J. Pharm. Biopharm. 48(1999) 101-111. Polymeric micelles are characterized by a core-shell structure consisting of hydrophobic inner core and hydrophilic outer shell. A poorly water soluble drug is entrapped within the hydrophobic core of the micelle. There are two typical methods of entrapping a poorly water soluble drug in the hydrophobic core of a micelle: a) a block copolymer and a poorly water soluble drug are dissolved in a water-miscible organic solvent, such as ethanol or N,N-dimethyl formamide(DMF), and the solution is dialyzed in water (Dialysis Method); and b) a drug solution of a water-immiscible organic solvent, such as dichloromethane or chloroform, is added to an aqueous polymeric solution and the organic solvent is evaporated from the solution mixture (O/W Emulsion-Solvent Evaporation Method).
Yokoyama et al. discloses methods of incorporating a poorly water soluble drug into the inner core of a polymeric micelle using an A-B type diblock copolymer composed of a hydrophilic methoxypolyethylene glycol block(A) and a hydrophobic polyamino acid(B). See U.S. Pat. Nos. 5,510,103 and 5,449,513. According to those patents, an aqueous micellar solution of the diblock copolymer and an organic solvent solution of the hydrophobic component are prepared in separate containers. The two solutions are then mixed and simply stirred, heated or sonicated to incorporate the hydrophobic drug into the polymeric micelles. The aqueous polymer solution and the drug solution in DMF are mixed together and the mixture is dialyzed against an excess of water. These methods require preparing an aqueous micellar solution prior to incorporating a drug into the polymeric micelle. See also, G. Kwon, et al., Block copolymer micelles for drug delivery: loading and release of doxorubicin, J. Contr. Rel. 48(1997) 195˜201; G. Kwon, et al., Physical entrapment of Adriamycin in AB block copolymer micelles, Pharm. Res. 12(1995) 192˜195.
X. Zhang et al. reported that a polymeric micelle prepared with a diblock copolymer of poly(lactic acid) and monomethoxy poly(ethylene glycol) was useful as a carrier of paclitaxel. X. Zhang et al., Int. J. Pharm. 132(1996) 195-206. Shin et al. disclose a solubilization method for indomethacin using a diblock copolymer of poly(ethylene glycol) and polycaprolactone. I. Gyun Shin et al., J. Contr. Rel., 51(1998) 13-22. In these methods, a poorly water soluble drug is incorporated in a polymeric micelle wherein the polymers are biocompatible and biodegradable. According to their methods, a drug and a block copolymer are dissolved together in an organic solvent, especially in a water-miscible organic solvent, such as tetrahydrofuran or dimethyl formamide. The polymeric micelles are prepared by first dialyzing the solution in water and then freeze-drying the aqueous micellar solution. Alternatively, a solution of a polymer and drug in a water-miscible organic solvent, acetonitrile, is prepared. The organic solvent is slowly evaporated to give a homogeneous drug-polymer matrix and the matrix is then dispersed in an aqueous medium at about 60° C. to form the polymeric micelles. It is stated that a polymeric micelle containing the drug cannot be formed if an organic solvent other than an acetonitrile, such as chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, or tetrahydrofuran is used for dissolving the drug and polymer. The aqueous polymeric micellar solutions are prepared by heating, ultrasonic treatment, vortexing or mechanical mixing.
As described above, conventional solubilization methods for poorly water soluble drugs using polymeric micelles employs complicated steps including formation of an aqueous polymeric micellar solution containing a poorly water soluble drug, followed by preparation of a freeze-dried powder. Moreover, the powdered product must then be reconstituted so it is not possible to store the product in an aqueous solution for a prolonged period of time because of the hydrolyzable and biodegradable components in the polymer. Another disadvantage is that this method can not be applied to a polymer having a melting temperature below about 50° C. Furthermore, all existing methods for incorporating a drug into the micelle require using an organic solvent and preparing the polymeric micelles in an aqueous medium. It is very difficult to completely eliminate the organic solvent in the process of preparing a polymeric micelle or incorporating a drug into the micelle. In addition, the remaining organic solvent decreases the stability of the micelle in water and makes it difficult to control the release rate of the drug.